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Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies.

ABSTRACT: Applying a next-generation sequencing assay targeting 145 cancer-relevant genes in 40 colorectal cancer and 24 non-small cell lung cancer formalin-fixed paraffin-embedded tissue specimens identified at least one clinically relevant genomic alteration in 59% of the samples and revealed two gene fusions, C2orf44-ALK in a colorectal cancer sample and KIF5B-RET in a lung adenocarcinoma. Further screening of 561 lung adenocarcinomas identified 11 additional tumors with KIF5B-RET gene fusions (2.0%; 95% CI 0.8-3.1%). Cells expressing oncogenic KIF5B-RET are sensitive to multi-kinase inhibitors that inhibit RET.

SUBMITTER: Lipson D

PROVIDER: S-EPMC3916180 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies.

Lipson Doron D Capelletti Marzia M Yelensky Roman R Otto Geoff G Parker Alex A Jarosz Mirna M Curran John A JA Balasubramanian Sohail S Bloom Troy T Brennan Kristina W KW Donahue Amy A Downing Sean R SR Frampton Garrett M GM Garcia Lazaro L Juhn Frank F Mitchell Kathy C KC White Emily E White Jared J Zwirko Zac Z Peretz Tamar T Nechushtan Hovav H Soussan-Gutman Lior L Kim Jhingook J Sasaki Hidefumi H Kim Hyeong Ryul HR Park Seung-il SI Ercan Dalia D Sheehan Christine E CE Ross Jeffrey S JS Cronin Maureen T MT Jänne Pasi A PA Stephens Philip J PJ

Nature medicine 20120212 3

Applying a next-generation sequencing assay targeting 145 cancer-relevant genes in 40 colorectal cancer and 24 non-small cell lung cancer formalin-fixed paraffin-embedded tissue specimens identified at least one clinically relevant genomic alteration in 59% of the samples and revealed two gene fusions, C2orf44-ALK in a colorectal cancer sample and KIF5B-RET in a lung adenocarcinoma. Further screening of 561 lung adenocarcinomas identified 11 additional tumors with KIF5B-RET gene fusions (2.0%; 9 ...[more]

PMID: 22327622

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Project description:Approximately 50% of conventional inflammatory myofibroblastic tumors (IMTs) harbor ALK gene rearrangement and overexpress ALK. Recently, gene fusions involving other kinases have been implicated in the pathogenesis of IMT, including ROS1 and in 1 patient PDGFRB. However, it remains uncertain whether the emerging genotypes correlate with clinicopathologic characteristics of IMT. In this study, we expand the molecular investigation of IMT in a large cohort of different clinical presentations and analyze for potential genotype-phenotype associations. Criteria for inclusion in the study were typical morphology and tissue availability for molecular studies. The lack of ALK immunoreactivity was not an excluding factor. As overlapping gene fusions involving actionable kinases are emerging in both IMT and lung cancer, we set out to evaluate abnormalities in ALK, ROS1, PDGFRB, NTRK1, and RET by fluorescence in situ hybridization. In addition, next-generation paired-end RNA sequencing and FusionSeq algorithm was applied in 4 cases, which identified EML4-ALK fusions in 2 cases. Of the 62 IMTs (25 children and 37 adults), 35 (56%) showed ALK gene rearrangement. Of note, EML4-ALK inversion was noted in 7 (20%) cases, seen mainly in the lung and soft tissue of young children including 2 lesions from newborns. There were 6 (10%) ROS1-rearranged IMTs, all except 1 presenting in children, mainly in the lung and intra-abdominally and showed a distinctive fascicular growth of spindle cells with long cell processes, often positive for ROS1 immunohistochemistry. Two of the cases showed TFG-ROS1 fusions. Interestingly, 1 adult IMT revealed a RET gene rearrangement, a previously unreported finding. Our results show that 42/62 (68%) IMTs are characterized by kinase fusions, offering a rationale for targeted therapeutic strategies. Interestingly, 90% of fusion-negative IMTs were seen in adults, whereas >90% of pediatric IMT showed gene rearrangements. EML4-ALK inversion and ROS1 fusions emerge as common fusion abnormalities in IMT, closely recapitulating the pattern seen in lung cancer.

Dataset Information

Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies.

Publications

Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies.

Similar Datasets

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